Making Capecitabine Targeted Therapy for Breast Cancer: Which is the Role of Thymidine Phosphorylase?

Bonotto, Marta; Bozza, C.; Loreto, Carla Di; Osa, Etin-Osa O.; Poletto, Elena; Puglisi, Fabio

doi:10.1016/j.clbc.2012.10.002

Cited by 25 publications

(18 citation statements)

References 39 publications

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“…37 Several studies report a correlation between elevated TP (as measured by either IHC or ELISA) and benefit with high response rate in gastric cancer patients and breast cancer on capecitabine based therapy as well. [38][39][40][41][42][43] These findings support the potentially predictive role of TP and a promising marker that can give helpful information to benefit from capecitabine-based chemotherapy. Palmar-plantar erythordysesthesia (PPE) is the most common toxicity of capecitabine.…”

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confidence: 62%

Untitled

2016

IJPSR

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ABSTRACT:Capecitabine an oral prodrug of 5-fluorouracil is widely used for the treatment of variety of solid tumors, particularly colorectal cancer. However it is not devoid of toxicities and may limit therapy. A little is known about predictors of toxicity, response and survival in patients treated with capecitabine. The pharmacogenetic testing methods can identify such variants and thus indicate those patients who are at risk for adverse effects with capecitabine. Various studies have been carried out to assess the various genetic predictive and prognostic markers with treatment. The purpose of this review is to describe the comprehensive reports and draw conclusion with the available information on capecitabine pharmacogenetics and future directions on ongoing research. An extensive literature search was carried out on the genes encoding the enzymes involved in the metabolism of capecitabine. Overall, evidence indicates multiple genes associated with the response/toxicity with capecitabine therapy, however majority of reports indicate DPD deficiency as a source of life-threatening toxic effects. Hence, prospective studies correlating the enzymes and the concentration of the drug and its metabolites in the body are needed before validated SNP tests can enter routine clinical practice.

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confidence: 62%

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2016

IJPSR

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“…The 5-Fu cannot be metabolized into an active ingredient in the absence of appropriate intracellular enzymes. Oral capecitabine only works when it is metabolized to 5-Fu by thymidine phosphorylase, however, methylation of this enzyme-encoding gene can lead to drug resistance [50,51].…”

Section: Drug Transportation and Metabolismmentioning

confidence: 99%

Identifying therapeutic targets in gastric cancer: the current status and future direction

Yu¹,

Xie

2016

ABBS

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Gastric cancer is the third leading cause of cancer-related death worldwide. Our basic understanding of gastric cancer biology falls behind that of many other cancer types. Current standard treatment options for gastric cancer have not changed for the last 20 years. Thus, there is an urgent need to establish novel strategies to treat this deadly cancer. Successful clinical trials with Gleevec in CML and gastrointestinal stromal tumors have set up an example for targeted therapy of cancer. In this review, we will summarize major progress in classification, therapeutic options of gastric cancer. We will also discuss molecular mechanisms for drug resistance in gastric cancer. In addition, we will attempt to propose potential future directions in gastric cancer biology and drug targets.

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“…1; supplemental materials are available at http://jnm.snmjournals. org) (12). Capecitabine-based chemotherapies have been reported to be more effective in tumors expressing high TP levels (13)(14)(15)(16).…”

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confidence: 99%

The Thymidine Phosphorylase Imaging Agent ¹²³I-IIMU Predicts the Efficacy of Capecitabine

et al. 2016

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Recently, companion diagnostics with nuclear medicine techniques have been anticipated as more suitable means than biopsy for predicting treatment efficacy. The anticancer effect of capecitabine, an orally administered chemotherapeutic agent activated by thymidine phosphorylase (TP), is positively associated with tumor TP expression levels. This study aimed to assess whether TP imaging using a radiolabeled uracil derivative, 123 I-5-iodo-6-[(2-iminoimidazolidinyl)methyl]uracil ( 123 I-IIMU), could predict the efficacy of capecitabine treatment. Methods: Sensitivity to doxifluridine, a metabolite of capecitabine and direct substrate for TP, was assessed by watersoluble tetrazolium salt assays in vitro for 3 human colon cancer cell lines with different TP expression profiles. The intracellular uptake and retention of 123 I-IIMU were evaluated. Mice inoculated with each cell line were treated with capecitabine for 2 wk, and tumor growth was compared. In vivo distribution studies and SPECT/CT imaging of 123 I-IIMU were performed in inoculated mice. Results: In vitro experiments showed a positive relation between TP expression levels and doxifluridine sensitivity. In vitro studies revealed that intracellular uptake and retention of 123 I-IIMU were dependent on TP expression levels. In vivo experiments in inoculated mice showed that 123 I-IIMU accumulation in tumor tissue was in line with TP expression levels and susceptibility to capecitabine treatment. Moreover, SPECT/CT imaging of 123 I-IIMU in tumorinoculated mice showed that 123 I-IIMU reflects TP expression levels in tumor tissues. Conclusion: 123 I-IIMU could be used as an in vivo companion diagnostic for predicting the efficacy of capecitabine treatment.

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Making Capecitabine Targeted Therapy for Breast Cancer: Which is the Role of Thymidine Phosphorylase?

Cited by 25 publications

References 39 publications

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Identifying therapeutic targets in gastric cancer: the current status and future direction

The Thymidine Phosphorylase Imaging Agent ¹²³I-IIMU Predicts the Efficacy of Capecitabine

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Making Capecitabine Targeted Therapy for Breast Cancer: Which is the Role of Thymidine Phosphorylase?

Cited by 25 publications

References 39 publications

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Untitled

Identifying therapeutic targets in gastric cancer: the current status and future direction

The Thymidine Phosphorylase Imaging Agent 123I-IIMU Predicts the Efficacy of Capecitabine

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The Thymidine Phosphorylase Imaging Agent ¹²³I-IIMU Predicts the Efficacy of Capecitabine